Primary FSGS is a serious renal disease, accounting for nearly 10-15% of all pediatric and adult patients requiring chronic dialysis or transplantation. Not only is the incidence of this disease rising, especially in select ethnic groups such as Blacks and Hispanics, the etiology of FSGS remains obscure and there is no proven therapy that is safe and well tolerated. In response to this urgent situation, a national multicenter NIDDK-funded randomized clinical trial is underway to compare the efficacy of cyclosporine, the current standard of care, with a combination of MMF and oral dexamethasone pulses in patients with steroid-resistant FSGS. It is anticipated that a significant number of patients will be ineligible for this trial because of prior treatment with one of the test therapies or will fail to respond to the experimental treatment. Children and young adults with FSGS who fail to respond to therapy have a high risk of developing end stage renal disease. The disease progression is always accompanied by increasing scarring and fibrosis within the kidney parenchyma. There is a critical need to develop novel therapies to treat these refractory patients. This proposal will evaluate the safety and efficacy of three novel agents that may have the capacity to reduce renal fibrosis and slow the rate of deterioration of disease in patients with resistant FSGS. This Phased Innovation Award application is composed of two distinct sections. During the initial stage, the R21 Phase, the safety, tolerance, and pharmacokinetic profile of two novel therapies - a tumor necrosis factor-alpha (TNF-alpha antagonist) and a peroxisome proliferator activator receptor-gamma, (PPARgamma) agonist will be tested. In the second stage, the R33 phase, a randomized Phase II clinical trial will be performed to assess the efficacy of the TNF-alpha antagonist adalumimab, the PPAR-gamma agonist rosiglitazone, an anti-TGF-beta antibody GC1008, and optimal conservative medical therapy. The outcome of this study will guide the design of a formal Phase III randomized clinical trial. The infrastructure that is established for the performance of this R21/R33 project should prove useful for the efficient assessment of additional novel therapies that will be developed in the future for patients with primary FSGS.